Project P-4 will examine mechanisms, consequences, and reversibility of angiogenesis: lymphangiogenesis in chronic airway inflammation. Experiments will explore the role of remodeled blood vessels and lymphatic vessels in mucosal swelling and leukocyte influx. Cellular mechanisms will be studied in mouse models of regulated transgenic overexpression of VEGF, Mycoplasma pulmonis infection, and growth factor stimulation and inhibition. The overall concept is that angiogenesis and lymphangiogenesis are integral to the pathophysiology of inflammatory airway disease and thus provide potential therapeutic targets. Aim #1 focuses on the growth, remodeling, and regression of airway blood vessels. Our hypothesis here is that by targeting the gatekeeper function of blood vessels, reversal of angiogenesis would reduce mucosal edema and leukocyte influx. We will (i) identify sensitive readouts of vascular regression, (ii) explore strategies of reversing angiogenesis, (iii) determine the effects of reversal on blood vessel leakiness, cell influx, and airflow mechanics, and (iv) identify new vascular targets by gene expression profiling and in vivo phage display. Aim #2 addresses the cell biology of lymphangiogenesis in airway inflammation. This little studied and poorly understood topic has important relevance because mucosal lymphatics are key routes for clearance of extravasated fluid and migration of immune cells to lymph nodes. Compelling preliminary data show extensive lymphangiogenesis in mouse airways after M. pulmonis infection. Our hypothesis is that lymphangiogenesis is a natural feature of airway inflammation, and any impairment could exaggerate mucosal edema and airflow obstruction. The first step will be to characterize the lymphatics in normal airways and lymphangiogenesis in airway inflammation. The role of VEGFR-3 signaling in lymphangiogenesis will then be examined using novel agonists and antagonists. Subsequent experiments will determine whether impaired lymphatic drainage leads to bronchial lymphedema. By taking advantage of recent progress in elucidating the molecular basis of angiogenesis and lymphangiogenesis, these studies have the potential of identifying new approaches for treating inflammatory airway disease.